Methods and compositions for modulating cardiac contractility

• US 20060079475A1
• Filed: 04/07/2005
• Published: 04/13/2006
• Est. Priority Date: 04/08/2004
• Status: Active Grant

• Current Assignee: Sangamo Biosciences, Inc.
• Original Assignee: Sangamo Biosciences, Inc.
• Inventors: Zhang, H. Steve, Zhang, Lei
• Granted Patent: US 7,534,775 B2
• Time in Patent Office: Days
• US Class Current: 514/44.R
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: C07K 14/4703 Inhibitors; Suppressors

Abstract

Methods and compositions are provided for modulating cardiac contractility by regulating transcription of the phsopholamban gene using engineered zinc finger proteins.

Claims

1. A method for modulating cardiac contractility a subject, the method comprising:

introducing a nucleic acid into a subject, wherein the nucleic acid encodes a polypeptide, wherein the polypeptide comprises;

(i) a zinc finger DNA-binding domain that is engineered to bind to a target site in the phospholamban gene; and

(ii) a transcriptional repression domain;

such that the nucleic acid is expressed in one or more cells of the subject, whereby the polypeptide binds to the target site and represses transcription of the phospholamban gene.

2. The method of claim 1, wherein the zinc finger DNA-binding domain comprises six zinc fingers and the amino acid sequence of the recognition regions of the zinc fingers is as follows:

3. The method of claim 1, wherein the zinc finger DNA-binding domain comprises six zinc fingers and the amino acid sequence of the recognition regions of the zinc fingers is as follows:

6. The method of claim 1, wherein the transcriptional repression domain is a KOX domain.

4. A polynucleotide encoding a protein comprising an engineered zinc finger DNA-binding domain, wherein the DNA-binding domain comprises six zinc fingers and the amino acid sequence of the recognition regions of the zinc fingers is as follows:

5. A polynucleotide encoding a protein comprising an engineered zinc finger DNA-binding domain, wherein the DNA-binding domain comprises six zinc fingers and the amino acid sequence of the recognition regions of the zinc fingers is as follows: